This project aims to identify abnormalities in brain function that contribute to dependence on drugs, and to offer leads in developing new treatment modalities. Our strategies include evaluating the relationship between cocaine craving and brain function and between risk taking and brain function in cocaine abusers as measured by positron emission tomography (PET) and [F-18]fluorodeoxyglucose; the relationship between risk taking and brain function and between the ability to inhibit inappropriate responses and brain function using PET and [O-15]water; and determining cognitive effects of nicotine on brain function using the [0-15]-water PET to measure cerebral blood flow. Consistent with findings of a smaller total volume of the prefrontal lobe in substance abusers compared to controls, we found that polydrug abusers (n=30) performed significantly more poorly than controls (n=24) on a risk taking task that is sensitive to orbitofrontal damage in humans, but not on the Wisconsin Card Sorting Task, a standard neuropsychological test of frontal cortical function. Furthermore, in PET studies measuring brain activation during the performance of the risk taking task, drug abusers show less activation in the orbital frontal cortex than control subjects. These data suggest that polydrug abuse is associated with functional deficits in specific portions of the prefrontal cortex. An evaluation of the effects of nicotine on brain function, as measured by PET with [O-15]-water showed that memory performance in 12 abstinent (12 h) nicotine-dependent smokers seems to be mediated by different neural substrates than those in 12 non-dependent controls, suggesting that chronic exposure to nicotine alters cognitive strategies or neural systems subserving memory. Regional activation during performance of a working memory task (N-Back test) was increased by nicotine in controls, but not in smokers, suggesting the development of tolerance.